Understanding mechanisms associated with chronic or persistent pain is important in developing therapeutic strategies. PSD-93/chapsyn-110 is a neuronal PDZ domain-containing protein that binds to and clusters NMDA receptors at synapses, and assembles a specific set of signaling proteins around the NMDA receptors. This proposal is focused on the interaction between the PSD-93/chapsyn-110 PDZ domain and NMDA receptors in central mechanisms of chronic or persistent pain. We have made the novel discoveries that 1) PSD-93/chapsyn-110 is expressed mainly in the superficial dorsal horn of spinal cord, where it co-localizes and interacts with NMDA receptors, and 2) targeted disruption of the PSD-93/chapsyn-110 gene significantly attenuates NMDA receptor-mediated excitatory postsynaptic currents in spinal dorsal horn neurons and reduces pain hypersensitivity triggered via NMDA receptor activation. This proposal seeks to further determine the role of PSD-93/chapsyn-110 in chronic or persistent pain, and explores cellular and molecular mechanisms of antinociception resulting from the deletion ofPSD-93/chapsyn-110 in chronic pain states. We will define whether knockout and knockdown of the PSD-93/chapsyn-110 affect thermal and mechanical pain hypersensitivity in complete Freund's adjuvant-induced inflammatory and nerve injury-induced neuropathic pain models. We will determine, in chronic pain states, the effect of PSD-93/chapsyn-110 deletion on NMDA receptor mediated excitatory sensory synaptic potentials, and on NMDA receptor-mediated response to peripheral noxious stimulation and to electrical stimulation-induced wind-up in spinal dorsal horn neurons. In wild type and PSD- 93/chapsyn-110 knockout mice, we will compare surface expression and synaptic localization of NMDA receptors in spinal cord neurons. These studies will provide a novel insight to the mechanisms of chronic pain and a new and potential biochemical target for the prevention and therapy of chronic pain. [unreadable] [unreadable]